Drug resistance represents one of the most critical obstacles to clinical benefit for cancer patients. Due to the size and complexity of this challenge, we believe a collaborative team approach is critical and have assembled a team of drug resistance experts from three leading institutions (MGH, the Broad Institute, and MIT/Koch Institute) with an exceptional track record of impactful discoveries in this field. We propose an integrated full-spectrum translational platform?including liquid biopsy, patient-derived tumor models, exome and transcriptome sequencing of tumor tissue, rapid autopsy, functional genomic screens, innovative preclinical mouse models, and a high-throughput combination drug-screening platform covering the CTEP portfolio?to address critical principles of drug resistance across several major cancer types?lung, melanoma and GI cancers, which impact a large percentage of cancer patients. Overall, these three projects will focus on the common theme of bypass resistance mechanisms, a critical ad frequent mechanism of therapeutic resistance that can involve both genetic and adaptive resistance mechanisms that ?bypass? the effects of therapy, and which can drive both intrinsic and acquired resistance. To maximize the potential impact on cancer patients we will focus projects on three major tumor types?lung, melanoma and GI cancers?with each project integrating at least two tumor types. We will focus our projects on defining and overcoming key bypass resistance mechanisms to three of the most critical classes of cancer therapeutics: MAPK inhibitors, RTK inhibitors, and immune checkpoint inhibitors. While each project will focus on a specific therapy and at least two specific cancer types, we believe the overall program design can be readily applied to additional agents and molecularly-defined cancers, such that the ultimate impact of this work will go beyond the specific studies proposed and will serve as a ?blueprint? for critical discoveries related to drug resistance. We anticipate that these efforts will define a new standard in our mechanistic understanding of bypass resistance mechanisms and will lead to novel opportunities to overcome them in the clinic. Our proposed approach will provide a steady stream of novel therapeutic strategies involving CTEP agents and pathways for evaluation in future clinical trials, as well as new potential agents for the CTEP portfolio. We have also integrated cutting-edge strategies for real-time blood-based monitoring of response and resistance to help guide innovative trial design.